This invention relates to a process and apparatus for not invasively probing in real time oxygen metabolism in body organs by means of a combination of light and ultrasound.
In recent years, much effort has been devoted to find ways to non-invasively probe regions of the brain, without using MRI or CT, which involve long procedures and do not allow real time analysis, except, to some extent, in some exceptional cases. Low-cost, portable and easy-to-use devices have been based on near infrared spectroscopy of blood, which have found some use by physicians. However, such techniques only provide a global picture of the brain without the minimum resolution which should allow a reliable diagnosis to be made.
Hemoglobin oxygenation gives an insight on the proper functioning of many body organs. This invention is particularly directed to probing hemoglobin oxygenation in the brain, but this is not intended as a limitation, and the invention includes probing in similar ways other organs, such as breast, liver, heart, and so on.
Light propagating inside a scattering medium has two componentsxe2x80x94ballistic and diffuse light. The first component does not experience scattering, while the second corresponds to strongly multi-scattered light (see M. Kempe, M. Larionov, D. Zaslatski and A. Z. Genack, Acousto-optic tomography with multiply scattered light, J. Opt. Soc. A., 14, 5, 1151 (1997)). Ballistic light decreases exponentially with distance in a scattering medium, whereas diffuse light remains roughly at the same relatively high intensity level. Therefore, diffuse light can give information to scattering medium deep inside it.
It is known in the art that information on the optical properties of the medium can be obtained by means of the said diffuse light, by focusing an ultrasound wave inside the medium at the particular region under examination. This phenomenon is exploited in U.S. Pat. No. 5,212,667 for the purpose of light-imaging in a scattering medium. Coherent light, generated as a laser beam and expanded by a beam expander, is projected into a scattering medium disposed between two parallel surfaces, in a direction perpendicular to said surfaces. Light emerging from it is a superposition of a multitude of scattered wavelets, each of which represent a specific scattering part. These wavelets are projected onto the viewing plane of a two-dimensional photodetector array, where they interfere with each other, giving rise to a speckle pattern. Propagating ultrasound pulses into the scattering medium in a direction substantially parallel to said surfaces, and focusing it in the probed region, changes the position of the scatterers and this causes a change in the speckle pattern. By comparing speckle images with and without ultrasound pulse, light absorption properties of the probed region can be measured. This method, however, based as it is on a unidirectional laser beam, has a limited capability of providing information on the scattering medium, and particularly, does not permit to obtain the information in real time as to hemoglobin oxygenation. Further, it does not permit to retrieve local hemoglobin oxygenation. U.S. Pat. No. 5,212,667 does not provide any algorithm showing how to retrieve such information. In fact, if only on-axis illumination is used, that is to say, the laser source, the ultrasound probe and the detector, are on the same line, modifying the position of the ultrasound probe does not allow to determine the local changes in absorption, because the absorption has to be integrated over the whole line.
If an ultrasound wave is focused inside a scattering medium and concurrently a continuous wave laser light beam crosses said medium and is strongly diffused thereby, light frequency is shifted by the ultrasound frequency (Doppler Effect) at the region of the focused ultrasound. At the other regions, the frequency of the light is practically unchanged, and consequently, the detection of the frequency-shifted light gives direct information on the optical properties of the region under test.
U.S. Pat. No. 5,212,667 is not concerned with changes in the speckle pattern. It states that, in the region in which the ultrasound is focused, the light-scattering properties are altered, owing either to change in the index of refraction induced by the pressure fluctuation of the ultrasound pulse, or by the changes in location of the scattering centers induced by such a pulse; and consequently, the speckle intensities in the focal plane are altered. The inventors submit that the magnitude of the speckle intensity change depends on the relative light absorption between the probed region and the surrounding medium. Other patents which refer to the tagging of light by the ultrasound are U.S. Pat. No. 5,174,298 and WO 95/33987. An article by Fay A. Marks et al, in SPIE, vol. 1888, p. 500, discusses the ultrasound tagging of light (UTL) as a tool for imaging breast tissue, and concludes that much work remains to be done to explore the feasibility of using UTL as a breast cancer imaging system.
The invention is based on the fact (see Ishimaru, A., Wave Propagation and Scattering in Random Media, Vol. 1, Academic Press (1978)) that hemoglobin can be found in the body in two different oxygenation statesxe2x80x94oxyhemoglobin and deoxyhemoglobinxe2x80x94which have different light absorption spectra. In the near infrared (690 mm and above), the absorption coefficients of both states of hemoglobin are relatively low. At around 804 mm, both states have exactly the same absorption coefficient: this point is called xe2x80x9cthe isosbestic pointxe2x80x9d. Therefore, measurement of blood absorption at this wavelength gives a direct indication of the blood volume being tested. At longer wavelengths, the absorption is essentially due to oxyhemoglobin. For example, at or around light wavelengths of 1 micron, the oxyhemoglobin absorbs more than three times than the deoxyhemoglobin: therefore, absorption at this wavelength gives a direct indication of the ratio between the two states of hemoglobin. The absorption spectra of oxyhemoglobin and deoxyhemoglobin are illustrated in FIG. 2.
The invention is characterized by the fact that the probed region (the part of the body in which the degree of hemoglobin oxygenation is to be monitored) is irradiated with light, preferably with a wavelength between 690 and 900 nm, the light frequency is shifted by an ultrasound pulse, and the degree of hemoglobin oxygenation is determined from the change in the absorption obtained at the frequency shifted signal.
FIG. 1 schematically illustrates the interaction between diffuse light and a focused ultrasound wave. An emitter emits light of frequency xcfx89 into the probed region. An ultrasound beam, of frequency xcexa9US is focused onto the probed region. Ultrasound modulated light, having a shifted frequency xcfx89+xcexa9US, and non-modulated light having frequency xcfx89 are detected by a detector, which mixes them and generates a signal modulated at the ultrasound frequency. Hereinafter, the expression xe2x80x9cmodulated signalxe2x80x9d will means the signal, detected by the detector, representing the intensity of the ultrasound modulated light, and expression xe2x80x9cnon-modulated signalxe2x80x9d will means the signal, detected by the detector, representing the intensity of the light not modulated by the ultrasound. The word xe2x80x9csignalxe2x80x9d without specification, will include both the modulated and the non-modulated signal.
This invention, therefore, provides a method for determining the local oxygenation level of hemoglobin by comparing the absorption of an ultrasound frequency-shifted signal with the absorption of hemoglobin in different states of oxygenation, at several wavelengths. Diffuse light (optionally, but not necessarily, at the isosbestic point) experiences an absorption throughout regions of the body. If an ultrasound wave is focused in a part of the body, and the frequency of the light is changed, detectors outside the part of the body under examination can selectively detect the ultrasound-modulated light, viz. the light which has passed through the focal region of the ultrasound wave. The ratio between the modulated signal and the non-modulated signal is determined by the local absorption changes. The part of the body under examination, or xe2x80x9cthe probed regionxe2x80x9d, may be, for example, the brain.
The invention also comprises optionally monitoring the blood volume by irradiating the probed region with light at the isosbestic point, detecting the light that is not absorbed, and determining the blood volume from the amount of light that is absorbed.
The method for determining the degree of oxygenation of hemoglobin, particularly comprises the steps of:
1xe2x80x94Irradiating the probed region with diffuse near-infrared light, preferably in the 690 to 900 nm wavelength range;
2xe2x80x94Generating at least an ultrasound wave, chosen from among continuous, pulse or burst waves;
3xe2x80x94Focusing said ultrasound wave in at least a region of the probed region;
4xe2x80x94Detecting light modulated by the ultrasound, originating from ultrasound focus region, for each light wavelength;
5xe2x80x94Determining the absorption of said modulated light by said probed region; and
6xe2x80x94Calculating from said absorption the degree of hemoglobin oxygenation in the probed region.
In a preferred embodiment of the invention, directed to monitoring the changes in the degree of oxygenation of hemoglobin in the probed region, the method comprises the steps of:
1xe2x80x94Irradiating the probed region with diffuse near-infrared light, preferably in the 690 to 900 nm wavelength range, using one or more wavelengths, but preferably two wavelengths, one below and one above the isosbestic point.
2xe2x80x94Generating at least an ultrasound wave, chosen from among continuous, pulse or burst waves;
3xe2x80x94Focusing said ultrasound wave in at least a region of the probed region;
4xe2x80x94Detecting light modulated by the ultrasound, originating from ultrasound focus region, for each light wavelength;
5xe2x80x94Determining the changes in the absorption of said modulated light caused by local changes in said probed region;
6xe2x80x94Calculating from said changes the changes of the degree of hemoglobin oxygenation in the probed region; and, preferably,
7xe2x80x94Shifting the focus of the ultrasound beam, whereby successively selecting different probed regions; and
8xe2x80x94Repeating for each successively selected probed region the determination of the change in the light absorption and in the degree of hemoglobin oxygenation.
Non-modulated light originating from the probed region is detected together with the modulated light. This is highly desirable in order to remove the influence of global changes in the probed region by a normalization algorithm, as will be explained hereinafter.
While the distinction between diffuse and ballistic light is well known, as has been set forth hereinbefore, it can be further clarified by considering the transmission of light through a scattering medium as a function of the thickness of the medium. In a transparent, non-scattering medium, all the light is ballistic. In a transparent, strongly scattering medium, ballistic light decreases exponentially very strongly and diffuse light decreases linearly. In a transparent, strongly scattering, slightly absorbing medium, ballistic light decreases exponentially very strongly and diffuse light decreases almost linearly, a slight exponential decrease due to absorption also occurring. Light in a scattering medium comprises, therefore, both ballistic and diffuse light. At low values of said thickness, the transmission signal decreases exponentially, but after a certain threshold, it decreases partially linearly and partially exponential, but the exponential component is relatively weak in the wavelengths considered herein, so that the decrease can be considered as substantially linear. Said threshold defines a ballistic regime below it, and a diffuse regime above it.
The change in the absorption of said ultrasound modulated light in the probed region, due to changes in the oxygenation state of the hemoglobin, is represented by an analog signal, that can then be transformed to a digital signal, to be processed and, if desired, visualized. The modulated signal is proportional to the amplitude of the light passing through the probed region, from which the absorption is calculated: the modulated signal changes reflect changes of the intensity of the light passing through the probed region, which in turn reflects changes in the absorption in the probed region. The signal has a frequency between a few hundred and a few MHz. It can be processed in various ways, e.g.: a) through a Lock-In Amplifier, which automatically detects the signal at the ultrasound frequency and transforms it into a digital signal which is sent to processor means; b) through an analog-to-digital card with a sampling cycle high enough to sample effectively the signal at the ultrasound frequency, the digitized signal being transferred to a computer memory and then processed in order to retrieve the signal at the ultrasound frequency; c) through a spectrum analyzer, which directly gives the signal at the ultrasound frequency.
Generally speaking, two kinds of blood circulation coexist in tissues: laminar circulation in large veins/arteries, which follows the heart rhythm, and capillary circulation in the tissues, which has a typical frequency of 0.1 Hz. In monitoring oxygenation changes, data are typically taken every minute. It is important that laminar circulation should not contribute heavily to the data signal. Since laminar circulation has only frequencies in the order of 0.1 Hz, viz. fast components relative to the frequency at which the data are taken, the contribution of laminar circulation to said data can be integrated out. It is integrated out because the integration is carried out over one or several minutes, which is a long period compared to the time periods associated with the laminar circulation.